The present invention relates to human growth hormone therapy and to the cure of human disease through organ and tissue transplantation. The present invention includes a method for regenerating the human thymus to allow intrathymic transplantation and thereby the elimination of organ and tissue rejection. There are two variations of this method, one that employs growth hormone and one that employs agent that can substitute for growth hormone's thymus-regenerating effects. The former method has wide applicability beyond the transplantation of tissues and organs, because it involves the elimination of the most important side effects of growth hormone. Human growth hormone (HGH) has been recognized as a treatment for children of short stature or with renal failure, and has been a safe and effective treatment in most cases, but there are several reports that such children often experience hyperinsulinemia as a result of HGH administration. Further, HGH has been considered as a powerful approach to the treatment of human aging, but its widespread use is inhibited by its serious side effects, the most important of which is elevation of fasting and glucose-stimulated insulin levels, a phenomenon that is known to be a risk factor for atherosclerosis and cardiovascular disease. Arginine, an HGH releaser, has therapeutic effects in its own right, but has the same drawback of elevating blood insulin levels. The invention described here permits HGH therapy to be administered with no elevation in blood levels of insulin.
Much has been written of late about the growing excitement of anti-aging (gerolytic) therapies, including hormone replacement therapy with dehydroepiandrosterone (DHEA), melatonin, sex hormones, thyroid hormone, cortisol, or human growth hormone. Of these, the work of Rudman has attracted the most attention because of his statement that administration of human growth hormone (HGH) produced the same effects as the reversal of 20 years of aging. Rudman and others have, in fact, amassed an impressive body of evidence indicating that it is the loss of HGH with age that is responsible for much of the human aging process, including atrophy of internal body organs, thinning of the skin, slowing of cell division, weakening of muscles and bones, and accumulation of body fat. Even immune system decline with age seems largely dependent on loss of HGH. Furthermore, GH administration to animals produces a radical increase in longevity.
On the other hand, Marcus et al. have shown the down side of HGH: given at the minimum doses used in Marcus' study, equivalent to the doses used by Rudman, HGH produced dramatic and disturbing rises in fasting and stimulated serum insulin levels. The administration of HGH is known to decrease the body's sensitivity (i.e., responsiveness) to insulin, thus causing a compensating rise in pancreatic insulin output and therefore in serum insulin levels; yet paradoxically, falling HGH levels in aging humans are accompanied by increasing serum insulin levels.
Elevated insulin, in turn, has been linked in many studies and via many mechanisms to the development of atherosclerosis, hypertension, and heart disease. It is absolutely a major factor holding back the widespread clinical application of HGH for combatting many of the maladies of aging, dimming the attraction of this otherwise spectacular anti-aging intervention. HGH also leads to mild rises in serum cholesterol and triglycerides, raises blood pressure, and may produce symptoms similar to arthritis.
Of all the developments in modem immunology that promise to make the rejection of transplanted cells, tissues, and organs obsolete, the most exciting is the technique of intrathymic transplantation pioneered by Naji et al. This is so because the method requires no specific attention to the details of the rejection process, can be applied to the transplantation of virtually any tissue or organ into virtually any recipient, probably including even transplantation between unrelated species, without complex tailor-made immunopharmaceuticals, and with minimal trauma to the recipient, and can reverse established autoimmune disorders including autoimmune diabetes. The method involves first transplanting a biopsy sample of the graft into the thymus of the recipient and then transplanting the graft itself after a predetermined time. The presence of the intrathymic biopsy renders the host tolerant to the graft itself, either by eliminating or anergizing immune cells that attack the biopsy in the thymus. In addition, it is likely that, in the case of autoimmunity, the host can be made tolerant of its own tissue again by transplanting it into the thymus, thus reversing autoimmunity. Contrary to the presumption that tolerization will require a longer time than the ex vivo lifetime of the graft to be transplanted, recent studies have shown that success can be achieved when kidneys are transplanted into the recipient within 24 hours of the time the renal biopsy is placed into the recipient's thymus. Rejection is suppressed in the short run by a single dose of antilymphocyte globulin and/or by other conventional immunosuppression until tolerization makes further immunosuppression unnecessary. Bone marrow transplantation is also believed to induce tolerance to subsequent grafts from the same donor by the migration of bone marrow cells into the thymus, an equivalent process to transplantation of actual organ tissue samples in the thymus.
The main problem with this method is that it requires a functioning thymus gland of significant mass in order To be effective. The human thymus begins to involute before the age of 20 and becomes severely atrophied by the age of 40, and transplant surgeons and immunologists are at a loss for a way of overcoming this problem. In fact, it is thought that age-related thymic involution accounts for a major part of age-related morbidity and mortality and therefore represents a major unsolved health problem worthy of solution in its own right.
What has not been recognized by the medical community is that thymic regeneration is possible in humans. Many animal studies attest to the feasibility of thymic regeneration in animals using several different methods. Several human studies have shown that immune system function can be restored in older humans, but it has never been suggested that this is due to thymic regeneration. The present invention effects thymic regeneration in man.
Several methods have been shown capable of reversing thymic involution in animals and, by inference, in man, but none are feasible for human use. Administering a male contraceptive to rats results in dramatic thymic regeneration, but would not be desirable in humans for a variety of reasons, including major testicular shrinkage. It has been recognized that hyperthyroid humans do not undergo age-related thymic involution, and that administration of thyroid hormone to older humans results in a restoration of youthful indices of immune system function, but administration of thyroid hormone is considered hazardous, and hyperthyroid individuals have a number of medical problems. The problems of regenerating the thymus of diabetic animals or humans have not been considered at all in the prior art.
As noted above, the use of growth hormone alone for this purpose would be contraindicated by the adverse effect of growth hormone on insulin sensitivity, despite the ability of growth hormone to regenerate the thymus in rodents and dogs and to improve immunity in older humans. Growth hormone use for thymic regeneration could lead to unacceptable loss of control of insulin responsiveness in diabetics and elevated insulin levels in nondiabetics. In fact, since elevated insulin leads to virtually all of the side effects of growth hormone (hypertension, atherosclerosis, water retention, and cardiovascular morbidity), it is possible that most of these side effects are a result, at least in part, of the elevation of insulin produced by growth hormone.